PROJECT SUMMARY/ABSTRACT The integrated system requested for this proposal is in vivo optogenetics, which combines optogenetic technology with behavioral tools. This innovative technology allows the investigators to control the activity of specific neurons through optogenetic manipulation to study their downstream influence on a variety of biological processes. Optogenetics has made a profound impact on the research of neuroscience. Optogenetic technologies to alter neuronal firing and function with light, combined with cell-type specific transgenic animal lines, is increasingly used as a novel tool to study neurological disorders and psychiatric diseases, including Alzheimer's disease (AD), traumatic brain injury (TBI), drug addiction and depression. At the Bronx James J. Peters Medical Center, groups of scientists are focusing on investigations of neurological and psychological disorders that have important implications in the Veteran population. Dr. Giulio Maria Pasinetti is currently developing new studies exploring the role of sleep deprivation (SD), a major issue in the Veteran population, in particular in subjects with post-traumatic stress disorder (PTSD), in altered cognitive function. The requested equipment will enable Dr. Pasinetti to use novel optogenetic technology to investigate how select compounds may modulate SD-mediated memory consolidation deficits in susceptible brain regions important for memory function, such as the hippocampal formation. Similarly, Dr. Dongming Cai will use in vivo optogenetic testing to investigate changes in memory function associated with motor proteins, such as dynamin and synaptojanin, in the pathogenesis of AD. Dr. Jun Wang is developing a new program in collaboration with Dr. Pasinetti on depression and anxiety, which are associated with maladaptation of synaptic plasticity in the medium spiny neurons (MSNs) in the nucleus accumbens (NAc). The NAc contains two subtypes of GABAergic projection neurons: dopamine D1 and D2 receptor-containing MSNs. The proposed optogenetic techniques will allow Drs. Wang and Pasinetti to address the selective contributions of NAc D1 and D2 neurons in stress-induced depression phenotypes. Moreover, by selective optogenetic stimulation of D1 and D2 MSNs, the investigators can further examine how mechanistically the novel intervention may differentially influence these two subpopulations of neurons in the NAc and provide resilience against depression/anxiety. Dr. Gregory Elder's project is to investigate the neurobiology of blast-related brain injury in a rat model of mild (m)TBI. It has been shown that the amygdala and related regions including the prefrontal cortex and hippocampus are keys in the development of TBI-induced PTSD. These structures are implicated in mediating fear responses in humans and animals as well. The proposed optogenetic techniques will provide novel means to elucidate the role of the amygdala in regulating motivational responses, fear and memory in relation to other structures. Dr. Fatemeh Haghighi, in collaboration with Dr. Elder, is investigating the epigenetic mechanisms that may contribute to TBI- induced neurological disorders. Collectively, the application for the acquirement of in vivo optogenetic tools combined with the available neurobehavioral core at the JJPVA will allow the proponents of this application to clarify the molecular mechanisms to identify the contributions of the amygdala, hippocampus, neocortex and other neural circuits to cognitive impairments under pathological conditions and provide novel therapeutic targets for preventing and treating physiological and interconnected degenerative conditions relevant to the VA mission, including SD-induced cognitive impairment, mood disorders, AD and TBI. In summary, the acquirement of the in vivo optogenetic system will provide a fundamental molecular tool to the existing behavioral facility and can be adapted to an extensive landscape of questions within neuroscience. We strongly believe that all investigators at the Bronx VA Health Center can benefit from this novel technology.